p38 protein kinase is a member of a family of signaling molecules known as the mitogen-activated protein kinase (MAPK) family, a family of Ser/Thr kinases which are responsible for a number of cell processes such as cell growth, proliferation, cell death and differentiation in response to a wide range of stimuli. The p38 subfamily responds to a number of stress stimuli, for example, ultraviolet light, osmotic shock, heat, and inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β).
p38 MAPK plays an important role in very diverse processes, such as in inflammation, cell differentiation (for example, myoblast-myotube conversion, preadipocyte cell differentiation, thymocyte differentiation, etc.), in the regulation of cell migration in response to various stimuli (for example, endothelial cell migration stimulated by endothelial growth factor (VEGF), etc.), and in cell cycle (in which the p38-MK2 pathway regulates the G2/M checkpoint in response to ultraviolet light or the G0 and G1/S checkpoints).
p38 MAPK pathway dysfunction has been correlated with the etiology and/or development of various pathologies, among which rheumatoid arthritis, psoriasis, heart failure, diabetes and even Alzheimer's disease are found. Recently, the role of p38 MAPK has been linked particularly to multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). p38 MAPK has therefore become an important therapeutic target. By way of illustration, the use of various p38 MAPK inhibitors has been described in the treatment of respiratory diseases (EP 1534282), autoimmune diseases such as rheumatoid arthritis, psoriasis or Crohn's disease (WO 2004/014387), pain (WO 2004/021988, US2008/0039461), cardiovascular diseases (WO 2005/032551) and in weight loss or the treatment of obesity (US2009/0074676). In a general review of p38 MAPK inhibitors and their effects on inflammation, B. Kamiska (Kamiska B., Biochimica et Biophysica Acta, 2005, 1754, 253-262) describes the inhibitory effect of compound SB 203580 [4-[4-(4-fluorophenyl)-2-(4-(methylsulfinylphenyl)-1H-imidazol-5-yl]pyridine], which is potentially useful as an anti-inflammatory agent in the treatment of rheumatoid arthritis, on p38 MAPK.
With respect to the role of p38 MAPK in multiple sclerosis (MS), Yasuda et al. (Yasuda et al., Cent New Syst Agents Med Chem., 2011, 11(1):45) describe that activation of the p38 cascade releases proinflammatory cytokines which are linked to this disease as well as to cerebral ischemia, Alzheimer's disease and Parkinson's disease. This study also describes new p38 MAPK inhibitors that are in phase II for the treatment of neuropathic pain and depression. p38α and p38β are known to be expressed in the brain and frequently activated in animal models of neurodegeneration, giving rise to the disturbance of physiological properties, activation of response genes and neurotoxicity (Harper et al., Expert Opin. Ther. Targets, 2003, 7: 187). The studies by Guo and Coulthard (Guo and Baht, Neurochemical Research, 2007, 32 (12) 2160; Coulthard et al., Trends in Mo. Med., 2009, 15(8):369) establish that the neuroprotective function of minocycline in animal models of MS and ischemia can be partly attributed to the inhibition of p38 MAPK signaling. On the other hand, the activation of p38 MAPK is necessary for the development and progression of chronic experimental allergic encephalomyelitis (EAE) and the relapsing-remitting course and the inhibition of p38 MAPK activity in T-cells is enough to modulate the severity of EAE (Noubade et al., Blood, 2011, 118(12):3290). Oral treatment with an ASK1 (p38 cascade activator) inhibitor suppressed EAE-induced inflammation in the spinal cord and in optic nerves (Guo et al., EMBO Mol Med, 2010, 2, 12:504) which corroborates the TLR-ASK1-p38 pathway in glial cells as a therapeutic target for demyelinating disorders such as multiple sclerosis.
With respect to the role of p38 MAPK in amyotrophic lateral sclerosis (ALS), the relationship between the aberrant expression of p38 MAPK and its activation in motor neurons and microglia for ALS progression must be highlighted (Bendotti et al., Neurodegener. Dis., 2005, 128). Furthermore, the continuous activation of p38 is correlated with motor neuron degeneration in transgenic mouse models of ALS (SOD1 mutant G93A) (Tortarolo M et al., Mol Cell Neurosci., 2003, 23(2); Holasek et al., Brain Res., 2005 1045:185), whereas a p38 MAPK inhibitor (SB203580) prevents SOD1 mutant-induced apoptosis of motor neurons (Dewil et al., Neurobiol. Dis., 2007, 26: 332). It has also been described that both p38 and JNK1 are involved in cytoskeletal abnormalities of spinal motor neurons, a characteristics of familial and sporadic ALS, through the aberrant phosphorylation and subsequent aggregation of neurofilaments (Bendotti et al., J. Neuropathol. Exp. Neurol., 2004, 63: 113; Ackerley et al., Mol. Cell. Neurosci., 2004, 26:354; Brownlees et al., J. Cell Sci., 2000 113: 401).
Although p38 MAPK inhibitors have been described, there is still a need to identify new compounds for inhibiting said kinase that are potentially useful in human therapy for the purpose of increasing the range of therapeutic approaches against p38 MAPK-regulated diseases that can be alleviated by means of inhibiting the biological activity of said p38 MAPK, particularly diseases presenting with local neuroinflammation or pain.
Document US 2005/0282818 describes heterocyclic compounds for inhibiting ubiquitin ligase, where said compounds are described as potentially useful for (indirectly) regulating the activity of MAP kinases. These compounds include molecules with a benzoxadiazolyl phenyl amine structure.
Document WO 2010/083404 relates to various benzoxadiazoles that are capable of interfering with Myc and Max association and are therefore potentially useful in the treatment of proliferative diseases.
Document US 2010/0099683 relates to the use of DNA ligase inhibitors for the treatment of cancer, among which inhibitors some derivatives with a benzoxadiazole structure are found.
Documents WO 2001/05390 and WO 2000/042022 describe compounds for inhibiting MEK kinase for the treatment of chronic pain and proliferative diseases, respectively. These documents include examples with a benzoxadiazole structure substituted with a group derived from carboxylic acid.